Pediatric drug development: 'A field in maturation’.

Reproductive Toxicology and Pharmaceutical Toxicology spring symposium

On the 24th of March 2016, the sections on Reproductive Toxicology and Pharmaceutical Toxicology organized a spring symposium entitled: ‘Pediatric drug development: a field in maturation’.

The invited speakers shared an overview of the latest insights on risk assessment of pediatric drugs from various perspectives. After a word of welcome, Saskia de Wildt kicked off the program with her presentation ‘Developmental Pharmacology: setting the stage’. Of the existing drugs on the market, there are still few drugs that are investigated for children. This has resulted in a diversity of dose recommendations for children through the years. In the Dutch Pediatric Formulary, the diverse dose recommendations have been combined in a single uniform dosing guideline. In the past, fatalities have occurred with ‘adult’ drugs in the pediatric patient population. Exposure might be diff erent in children, e.g. due to the ontogeny of the metabolizing enzymes and transporters, distribution volume, organ development. In clinical practice, a way to determine clinical doses for children without the supporting juvenile toxicity data has been established, assuming that when similar exposures are reached in children this will result in similar clinical efficacy.

To address some of these concerns, juvenile animal studies are conducted, as the second speaker Jan Willem van der Laan explained. The studies are conducted according to regional guidelines. In the form of the ICH S11 Guideline, an international harmonisation is on its way. The impact of the juvenile animal studies and need for harmonisation is illustrated by an overview of anti-cancer drug development for children. In half of the studies new target organ toxicities were observed in juvenile animals. The exposure levels in the juvenile animals were often higher than in the adults, which may result in toxicities at lower dose levels. Species selection, dose regimen, dose-range finding studies, dose adaptation and age at start of dosing as well as dose duration are important aspects to consider.

Illustrative of the need to understand the pediatric-specific pharmacodynamic (PD) and pharmacokinetic (PK) properties of a specifi c pharmaceutical compound was the presentation provided by Catherijne Knibbe. In clinical practice, drugs are often dosed on a mg/kg basis. As pediatric patients can have a higher clearance of the drug/kg body weight, higher dose levels might be required in the pediatric age category for the desired PD effect. Population PK-PD modelling can help to predict the dose levels required in the pediatric population, needed to achieve the desired PD effect. This method allows for few samples per individual, while more individuals are needed. Individualized dosing guidelines for specific drugs can be established, while for compounds metabolized through the same pathways a ‘system’ approach could be envisioned.

The meeting continued (after a lunch break) with real-life examples presented by Graham Bailey. As the title of his presentation mentioned: expect the unexpected when conducting non-clinical juvenile animal studies. To list just some of the discussion points when designing a juvenile animal study: the age of the animals at the start of dosing should be representative of the relative developmental stage of the intended pediatric clinical population. Making a study more complicated rarely makes interpretation easier. As mentioned by previous speakers, the ontogeny of the drug metabolizing enzymes and transporters should be taken into accountincluding species differences. Don’t forget that guidelines should be considered as just one way of achieving an objective, they should never be followed rigidly if there is a good scientific justification not to.

But how to we deal with pharmaceuticals for the pediatric population from a quality perspective? Diana van Riet explained how adequate product quality relates to chemical quality, pharmaceutical quality, usability including patient acceptability, and user instruction. Assessment of child and parent preference and acceptability of different formulations (from tablet to liquid) has revealed that historical assumptions are not always accurate. Further, the excipients used in the adult formulation are not always appropriate for use in the pediatric population due to safety concerns. The European Paediatric Formulation Initiative (EuPFI) Safety & Toxicity of Excipients for Paediatric (STEP) initiative is useful source for information on safety of specific excipients. (

Once on the market, pharmaceuticals are carefully monitored for potential side eff ects. This pharmacovigilance, e.g. the monitoring of safety of pharmaceuticals after authorisation, was further detailed by Boukje Raemaekers. Information provided to the Netherlands Pharmacovigilance Centre (Lareb; can be in the form of spontaneous reports of suspected adverse drug reactions from either healthcare professionals or consumers. On the label of medicines, it is mentioned that side eff ects can be reported at Lareb. After careful assessment, signals of adverse drug reactions might result in regulatory actions, Dear Healthcare Professional (DHCP) letters, product information updates and/or educational materials.

Overall, the day as organised by the sections on Reproductive Toxicology and Pharmaceutical Toxicology provided an overview of pediatric medicines, from the view of the health care professional, researcher, up to the regulator. Furthermore, they provided food for thought, like what should be the focus of the juvenile toxicity testing: the changing pharmacodynamic target during development, or the differences in exposure between children and adults; PD versus PK. This was clearly visible from the lively discussions between the participants during the drinks at the end of the day.




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